Three novel uncharged silver carbene microbicides that have been shown to be effective against a wide variety of pathogens will be formulated into two different ointment formulations and tested in an infected healing model in the diabetic rat. Formulation of the silver carbenes into one of either a transparent (gel) wound ointment that will allow viewing of the wound while being treated or an occlusive petrolatum-based ointment that is anticipated to have different moisture retention and drug delivery characteristics that a water-based gel will be carried out. The major specific aims of the proposed research involve the preparation & formulation/processing of the silver carbene antimicrobial agents into an ointment form, chemical and biological characterization, determination of maximum tolerated doses, and evaluation in an infected wound model in the rat. The biological characterization involves the determination of the MIC90 for each compound and evaluation of the toxicity of each compound formulated into an ointment over a two log range starting at a concentration (in the ointment) at the MIC90. The primary objectives of the proposed therapy are: 1) resolution of infection, 2) minimization of inflammation, and 3) encouragement of wound resolution. This innovative and rational approach to a topical antimicrobial therapy is founded on the basis of several different studies that have revealed promising bio-applicable attributes of these silver carbene complexes. The end-goal of this project is to enable the next phase of development of one or more of these novel microbicidal compounds that will be targeted for the treatment of infected chronic wounds and burns while developing a greater understanding of the mechanisms by which these compounds work. PUBLIC HEALTH RELEVANCE: Diabetic foot ulcers are a common type of chronic wound affecting as many as 25% of all diabetics and in many cases diabetics develop infection as a consequence of an impaired inflammatory response. Infection can greatly complicate treatment and outcomes for diabetic foot ulcers with 65% of all patients developing osteomyelitis and amputation in 14-24% of the osteomyelitis group (American Diabetes Association, 1999). Complications associated with foot ulcers account for 20-25% of all hospitalizations costing billions of dollars annually and despite the important medical advances that have been made in the treatment of diabetic foot ulcers in the past fifty years, there remains a significant need for more effective therapies to combat infection and impaired wound healing in this patient population.